Reactive oxygen species (ROS) are produced constantly inside the cells as a consequence of nutrient catabolism. The balance between ROS production and elimination allows to maintain cell redox homeostasis and biological functions, avoiding the occurrence of oxidative distress causing irreversible oxidative damages. A fundamental player in this fine balance is reduced glutathione (GSH), required for the scavenging of ROS as well as of the reactive 2-oxoaldehydes methylglyoxal (MGO). MGO is a cytotoxic compound formed constitutively as byproduct of nutrient catabolism, and in particular of glycolysis, detoxified in a GSH-dependent manner by the glyoxalase pathway consisting in glyoxalase I and glyoxalase II reactions. A physiological increase in ROS production (oxidative eustress, OxeS) is promptly signaled by the decrease of cellular GSH/GSSG ratio which can induce the reversible S-glutathionylation of key proteins aimed at restoring the redox balance. An increase in MGO level also occurs under oxidative stress (OxS) conditions probably due to several events among which the decrease in GSH level and/or the bottleneck of glycolysis caused by the reversible S-glutathionylation and inhibition of glyceraldehyde-3-phosphate dehydrogenase. In the present review, it is shown how MGO can play a role as a stress signaling molecule in response to OxeS, contributing to the coordination of cell metabolism with gene expression by the glycation of specific proteins. Moreover, it is highlighted how the products of MGO metabolism, S-D-lactoylglutathione (SLG) and D-lactate, which can be taken up and metabolized by mitochondria, could play important roles in cell response to OxS, contributing to cytosol-mitochondria crosstalk, cytosolic and mitochondrial GSH pools, energy production, and the restoration of the GSH/GSSG ratio. The role for SLG and glyoxalase II in the regulation of protein function through S-glutathionylation under OxS conditions is also discussed. Overall, the data reported here stress the need for further studies aimed at understanding what role the evolutionary-conserved MGO formation and metabolism can play in cell signaling and response to OxS conditions, the aberration of which may importantly contribute to the pathogenesis of diseases associated to elevated OxS.

Background: Curcumin is a yellow-orange pigment obtained from the plant Curcuma longa, which is known to exert beneficial effects in several diseases, including cancer. However, at high doses, it may produce toxic and carcinogenic effects in normal cells. In this context, we studied the effects of curcumin on normal human dermal fibroblast (HDF) cells and breast cancer cells (MCF7). Methods: We used cellular viability and growth assays to evaluate the antiproliferative action of curcumin, analyzed the endogenous glutathione levels, conducted cell cycle, apoptosis, and necrosis analyses, and performed immunodetection of glutathionylated and acetylated H3 histones. Results: We found that HDFs are more sensitive to curcumin treatment than MCF7 cells, resulting in pronounced arrest of cell cycle progression and higher levels of cellular death. In both cell types, the homeostasis of the redox cellular environment did not change after curcumin treatment; however, significant differences were observed in glutathione (GSH) levels and in S-glutathionylation of H3 histones. Conclusion: Curcumin administration can potentially confer benefits, but high doses may be toxic. Thus, its use as a dietary supplement or in cancer therapies has a double edge.

Epigenetics encompasses reversible and heritable genomic changes in histones, DNA expression, and non-coding RNAs that occur without modifying the nucleotide DNA sequence. These changes play a critical role in modulating cell function in both healthy and pathological conditions. Dysregulated epigenetic mechanisms are implicated in various diseases, including cardiovascular disorders, neurodegenerative diseases, obesity, and mainly cancer. Therefore, to develop innovative therapeutic strategies, research for compounds able to modulate the complex epigenetic landscape of cancer is rapidly surging. Dietary phytochemicals, mostly flavonoids but also tetraterpenoids, organosulfur compounds, and isothiocyanates, represent biologically active molecules found in vegetables, fruits, medicinal plants, and beverages. These natural organic compounds exhibit epigenetic modulatory properties by influencing the activity of epigenetics key enzymes, such as DNA methyltransferases, histone acetyltransferases and deacetylases, and histone methyltransferases and demethylases. Due to the reversibility of the modifications that they induce, their minimal adverse effects, and their potent epigenetic regulatory activity, dietary phytochemicals hold significant promise as antitumor agents and warrant further investigation. This review aims to consolidate current data on the diverse epigenetic effects of the six major flavonoid subclasses, as well as other natural compounds, in the context of cancer. The goal is to identify new therapeutic epigenetic targets for drug development, whether as stand-alone treatments or in combination with conventional antitumor approaches.

Glyoxalase 2 is a mitochondrial and cytoplasmic protein belonging to the metallo-β-lactamase family encoded by the hydroxyacylglutathione hydrolase (HAGH) gene. This enzyme is the second enzyme of the glyoxalase system that is responsible for detoxification of the α-ketothaldehyde methylglyoxal in cells. The two enzymes glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2) form the complete glyoxalase pathway, which utilizes glutathione as cofactor in eukaryotic cells. The importance of Glo2 is highlighted by its ubiquitous distribution in prokaryotic and eukaryotic organisms. Its function in the system has been well defined, but in recent years, additional roles are emerging, especially those related to oxidative stress. This review focuses on Glo2 by considering its genetics, molecular and structural properties, its involvement in post-translational modifications and its interaction with specific metabolic pathways. The purpose of this review is to focus attention on an enzyme that, from the most recent studies, appears to play a role in multiple regulatory pathways that may be important in certain diseases such as cancer or oxidative stress-related diseases.

Glyoxalase II (GlxII) is an antioxidant glutathione-dependent enzyme, which catalyzes the hydrolysis of S-D-lactoylglutathione to form D-lactic acid and glutathione (GSH). The last product is the most important thiol reducing agent present in all eukaryotic cells that have mitochondria and chloroplasts. It is generally known that GSH plays a crucial role not only in the cellular redox state but also in various cellular processes. One of them is protein S-glutathionylation, a process that can occur through an oxidation reaction of proteins’ thiol groups by GSH. Changes in protein S-glutathionylation have been associated with a range of human diseases such as diabetes, cardiovascular and pulmonary diseases, neurodegenerative diseases and cancer. Within a major project aimed at elucidating the role of GlxII in the mechanism of S-glutathionylation, a reliable computational protocol consisting of a protein–protein docking approach followed by atomistic Molecular Dynamics (MD) simulations was developed and it was applied to the prediction of molecular associations between human GlxII (in the presence and absence of GSH) and some proteins that are known to be S-glutathionylated in vitro, such as actin, malate dehydrogenase (MDH) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The computational results show a high propensity of GlxII to interact with actin and MDH through its active site and a high stability of the GlxII–protein systems when GSH is present. Moreover, close proximities of GSH with actin and MDH cysteine residues have been found, suggesting that GlxII could be able to perform protein S-glutathionylation by using the GSH molecule present in its catalytic site.

The increasing availability of molecular data provided by next-generation sequencing (NGS) techniques is allowing improvement in the possibilities of diagnosis and prognosis in renal cancer. Reliable and accurate predictors based on selected gene panels are urgently needed for better stratification of renal cell carcinoma (RCC) patients in order to define a personalized treatment plan. Artificial intelligence (AI) algorithms are currently in development for this purpose. Here, we reviewed studies that developed predictors based on AI algorithms for diagnosis and prognosis in renal cancer and we compared them with non-AI-based predictors. Comparing study results, it emerges that the AI prediction performance is good and slightly better than non-AI-based ones. However, there have been only minor improvements in AI predictors in terms of accuracy and the area under the receiver operating curve (AUC) over the last decade and the number of genes used had little influence on these indices. Furthermore, we highlight that different studies having the same goal obtain similar performance despite the fact they use different discriminating genes. This is surprising because genes related to the diagnosis or prognosis are expected to be tumor-specific and independent of selection methods and algorithms. The performance of these predictors will be better with the improvement in the learning methods, as the number of cases increases and by using different types of input data (e.g., non-coding RNAs, proteomic and metabolic). This will allow for more precise identification, classification and staging of cancerous lesions which will be less affected by interpathologist variability.